Alterations of cerebral white matter structure in psychosis and their clinical correlations: a systematic review of Diffusion Tensor
Imaging studies

Alterazioni strutturali della sostanza bianca cerebrale nella psicosi e le relative correlazioni cliniche: una rassegna sistematica degli studi di diffusion
tensor imaging

Serena PARNANZONE1, Dario SERRONE1, maria cristina ROSSETTI1, SIMONA D’ONOFRIO1, alessandra splendiani2, valeria micelli2, ALESSANDRO ROSSI1, FRANCESCA PACITTI1
E-mail: francesca.pacitti@cc.univaq.it

1Department of Biotechnological and Applied Clinical Sciences (DISCAB), University of L’Aquila, Italy
2Department of Biothecnological and Applied Clinical Sciences (DISCAB), Neuroradiological Unit, University of L’Aquila, Italy


SUMMARY. Schizophrenia is a common, severe and chronically disabling mental illness. Most of MRI studies in schizophrenia suggest the involvement of white matter (WM) pathology in multiple cerebral regions in the neurobiology of this condition. White matter fiber tracts connecting numerous cortical regions have been the focus of a number of studies using a magnetic resonance technique called “Diffusion Tensor Imaging” (DTI). A literature search of published DTI studies was conducted using the major database National Centre for Biotechnology information (NCBI) PubMed (MEDLINE). Our review covers 95 published papers. We summarise the main DTI findings involving the different brain regions in patients affected by or at high-risk for psychosis; we discuss clinical implications of these white matter disruptions and the limitations of current studies, listing the potential confounds and suggesting potential future research directions.

Key Words: DTI, psychosis, schizophrenia, white matter.


RIASSUNTO. La schizofrenia è una malattia mentale comune, grave e cronicamente invalidante. La maggior parte degli studi di risonanza magnetica in pazienti affetti da schizofrenia suggerisce il coinvolgimento della sostanza bianca di diverse regioni cerebrali nella patogenesi e nella neurobiologia di questa malattia. I fasci di sostanza bianca interposti tra le diverse regioni corticali sono stati oggetto di numerosi studi che utilizzano una tecnica di risonanza magnetica chiamata “Diffusion Tensor Imaging” (DTI). Nel presente studio è stata condotta una revisione della letteratura sugli studi di DTI pubblicati utilizzando il database National Centre for Biotechnology (NCBI) PubMed (Medline). Questa rassegna comprende 95 articoli pubblicati. Sono stati riportati i principali risultati degli studi di DTI in pazienti affetti da psicosi o ad alto rischio per lo sviluppo di psicosi; sono state discusse le implicazioni cliniche delle alterazioni della sostanza bianca e i limiti degli studi in corso elencando i potenziali fattori di confondimento e suggerendo possibili direzioni future per la ricerca.

Parole Chiave: DTI, psicosi, schizofrenia, sostanza bianca.

INTRODUCTON
Schizophrenia is a complex psychiatric syndrome comprising of psychiatric symptoms, including auditory hallucinations and delusions, cognitive deficits and social dysfunction1.
The majority of studies on structural brain changes in patients at ultra-high risk for or affected by psychosis have been based on magnetic resonance imaging. Brain structural MRI is based on the differential behaviour of protons of water molecules in gray and white matter when exposed to a variable magnetic field. The contrast between structures varying in the response to magnetic field alterations allows delineating local groupings of neurons and fibers and determining their sizes in absolute and relative terms 2.
Most of MRI studies in schizophrenia suggest the involvement of white matter (WM) pathology in multiple cerebral regions in the neurobiology of this condition. As normal brain functions are served by macrostructural circuits of cortical and subcortical areas, disturbed communication between brain regions may be the core pathology of psychosis. WM consists of the axonal projections to other neurons and functional brain areas and is therefore key to neural communication. Myelination is initiated prenatally and completed for most tracts within the first year birth but continues during childhood, adolescence and adulthood and has a region-specific course where prefrontal regions myelinate the last 3. Several lines of evidence point to myelin dysfunction, reduced oligodendrocyte number or integrity, or possibly hyperglutamatergic state4.
Neurodevelopmental theories have suggested demyelination during adolescence and adulthood to occur in psychosis.
Abnormalities in WM structure and integrity have been correlated with psychotic symptoms, negative symptoms and cognitive deficits5.
WM is difficult to study in detail with conventional MRI because of its high degree of homogeneity, moreover conventional techniques do not allow for the evaluation of its directionality and organization. WM fiber tracts connecting numerous cortical regions have been the focus of a number of studies using a magnetic resonance technique called Diffusion Tensor Imaging (DTI). It has become established in the last two decades as a valuable research tool. DTI assesses a non-invasive and in vivo quantification of the diffusion characteristics of water molecules: within a magnetic field these molecules tend to align into preferential directions according to their ability to diffuse across or along the arrangement of biological structures that surround them. In the brain water may diffuse freely in all directions (isotropic diffusion), or restricted along one particular direction of structured tissue such as WM tracts and fibers (anisotropy diffusion). Fractional anisotropy is a quantitative dimension and can take values between 0 and 1. If the anisotropy is high, then most of the diffusion occurs in the highly ordered directions, indicating a high level of orientation in the structure, therefore, decreased anisotropy may predict compromised white matter integrity 6. Other measures used to compare different voxels in term of diffusion are mean diffusivity (MD), radial diffusivity (RD) and relative anisotropy (RA)7. Additionally different approaches have been applied to study differences in regional brain anisotropy between subjects: some studies have used voxel based approaches (VBA), where data sets have been processed with reference to FA normalized to a standard anatomical and averaged template, before being compared to similarly processed data sets; other studies have used a region of interest (ROI) approach in region of the brain thought to be implicated to psychosis. DTI is becoming increasingly important in the field of schizophrenia research 8.
The aim of this study was to review the knowledge about the abnormalities of WM in patients at ultra-high risk for psychosis (UHR), patients with a first-episode psychosis (FEP) and chronic schizophrenia patients (SZ) compared with controls (HC), making clearer the role of WM integrity alterations in the etiopathogenesis, anatomical bases and clinical or neuro-cognitive correlates of the disorders.
METHODS
A literature search of published DTI studies was conducted using the major database National Centre for Biotechnology information (NCBI) PubMed (Medline).
The key words used were: “schizophrenia” and “ DTI” or “diffusion tensor imaging”, “psychosis” and “DTI” or “diffusion tensor imaging”. Studies were included if they satisfied the following criteria: the patient population had a diagnosis of psychosis or was considered at ultra-high risk for psychosis, diffusion tensor imaging was an imaging technique used, the article was published in English. Additionally, they were chosen if they were found to be relevant to the focus of this systematic review.
Our review covers 95 papers published between September 2005 and March 2015: 32 papers were excluded.
RESULTS
In 25 studies the patient population included people considered at ultra-high risk for psychosis. To be considered at high-risk for psychosis patients had to satisfy almost one of these criteria: 1) they had schizotypal personality features; 2) they had sub-threshold psychotic symptoms; 3) they had a first-degree relative with schizophrenia-like disorder; 4) they had brief psychotic moments with spontaneous remission in less than 1 week (Table 1).
We have decided to mention some of the studies excluded because they can provide additional information.
In a study was examined the ability of DTI to differentiate between UHR, FEP and HC subjects: the results suggest that DTI allowed discrimination of UHR from HC subjects34.
Patients with only cannabis use disorder (CUD) have also been studied with DTI method: they had lower FA than HC in left inferior FOF27, and altered FA values in left ILF and left inferior FOF compared to HC; greater consumption of cannabis predicted a greater decrease in left ILF FA in CUD35.
In the study by Mittal et al.36 youth at high-risk for psychosis presented neurological disfunction and abnormal neurodevelopment misured by the presence of neurological soft signs (NSS) and a decrease of FA in right/left superior CP at 12 months, controls showed a normative increase while there were no group differences at baseline. NSS predicted a longitudinal decrease in cerebellar-thalamic FA and elevations in negative but not positive symptoms 12 months later.
According to Derosse et al.37 cumulative risk for psychosis (including low QI, low parental socioeconomic status, history of adolescent cannabis use and childhood trauma, high levels of subclinical psychotic-like experiences) was associated with lower FA in left SLF.
In the study by Skranes et al.38 very low birth weight children had reduced FA values in CI, CE, CC, ILF, SLF; children with low QI had reduced FA in CE, SLF, ILF; fine motor impairment was related to low FA in CI, CE and SLF; mild social deficits correlated with reduced FA in CE and SLF.
Prenatal and neonatal DTI were obtained in the offspring of mothers with schizophrenia or schizoaffective disorder and matched comparison mothers: there were no group differences in white matter diffusion tensor properties39.
In 41 studies the patient population included people experiencing a first episode of psychosis. (Table 2)
According to Peters et al.75 FEP with cannabis use before age 17 showed increased directional coherence in the bilateral UF, anterior CI and FL while these abnormalities were absent in FEP without cannabis use before age 17: this is in contrast with most DTI studies which have produced evidence of WM hypoconnectivity.
In 46 studies the patient population included people with chronic schizophrenia (Table 3).
Tang et al.110 obtained DTI and magnetic resonance spectroscopy from 40 subjects with schizophrenia: N-Acetylaspartate and DTI anisotropy indices were reduced in medial temporal regions.
Patients with temporal lobe epilepsy and interictal psychosis were studied with DTI by Flügel et al.111; they showed lower FA values in both frontal and temporal regions and higher MD in bilateral frontal regions, additionally the performance on some neuropsychological tests was related to frontotemporal FA reduction. Mao et al.112 investigated interictal personality changes and white matter abnormalities in epilepsy patients: long disease duration and impairment of right AF integrity were independent risk factor of psychoticism.
Cocchi et al.113 studied the relationship between structural and functional deficits in schizophrenia patients: they showed decreased functional connectivity and impaired white matter integrity in a distributed network encompassing frontal, temporal, thalamic and striatal regions; in controls strong interregional coupling in neural activity was associated with well-myelinated white matter pathways.
Compared with Parkinson’s disease patients without psychosis, those with psychosis had significantly lower FA in left frontal lobe, bilateral occipital lobe, left cingulated gyrus and left hippocampus114.
For an overview of the results see table 4.







































DISCUSSION
The findings can be grouped into WM pathology affecting cortical regions, subcortical regions, inter-hemispheric fibers, association fibers and limbic system fibers. Corpus callosum consists of a commissural tract comprising the largest bundle of fibers connecting the two brain hemispheres.
Association fibers are: SLF which connects the frontal lobe with occipital and temporal areas, ILF, UF which are anterior temporo-frontal fiber tracts connecting orbito-frontal with anterior and medial temporal lobes, FOF which extends backward from the frontal lobe and spreading into the temporal and occipital lobes, AF is a fiber tract that stems from the caudal part of the superior temporal gyrus and extends to the lateral prefrontal cortex, the superior and the middle frontal regions. Limbic system fibers are the cyngulum fibers that project both posteriorly from the cingulate gyrus to the entorhinal cortex, temporal lobe, and anteriorly to the premotor, prefrontal regions and striatum. The fornix connects the hippocampus to the mamillary bodies, nucleus accumbens, medial prefrontal cortex, and septal regions, thus this fiber serves as the main output and input pathway for hippocampus. Thalamic radiations are projection fibers that provides a functional loop between the cerebral cortex and the thalamus; they converged into the internal capsule, located between the putamen and the thalamus-caudate nucleus regions 5.
Changes in WM integrity were found in chronic psychosis, first-episode psychosis and patients at ultra-high risk for psychosis, they may play a role in the primary pathophysiology, as opposed to being a result of secondary disease processes. These changes have been correlated with specific cognitive deficits as well as clinical symptoms, suggesting that biological changes may underlie these clinical factors in patients.
Previous DTI studies assessing the impact of WM disruptions on the disease process have had mixed results. Our study adds to a growing body of literature emphasizing the need for treatments targeting white matter function and structure in psychosis patients.
The main findings in patients at ultra-high risk for psychosis were a decreased FA in inferior FOF, temporal lobe WM, frontal lobe WM. They seem to have predictive value of onset of psychosis in high-risk individuals. Other studies in ultra-high risk patients showed lower FA in anterior CR, corticospinal tracts, SLF, ILF, UF, CC and C. In addition, increase of FA values was seen in anterior C, left UF, AF, frontal lobe WM, right fornix and brain stem. The prediction of psychosis is a major topic in research and olds the hope for early intervention and prevention of full development of the illness, improving outcome and preserving WM integrity.
Decreases of FA in different tracts in patients at first-episode psychosis support notion of early disconnectivity between brain regions: the most burned were CC, UF, ILF, SLF, inferior FOF, temporal lobe WM, parietal lobe WM and left frontal lobe WM. White matter abnormalities were also observed in C, occipital lobe, CI, corticospinal tracts, cerebral peduncles and fornix. None of the studies included showed increased FA in patients with first-episode psychosis.
DTI abnormalities in first-episode patients are less robust than in chronic patients, suggesting that progression to more extensive abnormalities occurs after illness onset; there are also indications for accelerated aging effects in psychosis.
FA reductions were found in patients with chronic psychosis in CC, C, UF, left ILF, inferior FOF, SLF, FMN, FMJ, CR, corticospinal tracts, anterior CI, TR, temporal lobe WM, occipital lobe WM and frontal lobe WM. Changes in WM integrity have been reported also in left AF, superior FOF, fornix and hippocampus.
White matter tracts that were reported to have increased FA in almost one study include brain stem, right frontal lobe WM, left occipital lobe WM, insula, CI, cerebellum, inter-hemispheric and cortico-cortical tracts.
Of the included studies, 13 did not report group differences in anisotropy measures between patients and controls (3 in ultra-high risk patients, 8 in first-episode psychosis, 2 in chronic psychosis).
38 of the included studies (7 in UHR, 12 in FEP, 19 in SZ) found significant correlations between clinical or cognitive variables and FA values in some WM tracts. 3 studies showed a negative correlation between the severity of positive symptoms and FA values in some WM tracts like temporal lobe WM, right anterior C, right frontal lobe WM, cingulated gyrus WM, left fornix, right anterior and posterior limb of CI, left UF, left SLF, fibers connecting the rostral with the caudal anterior CG, bilateral inter-hemispheric and cortico-cortical connections, cerebellum and brain stem. Regarding to hallucinatory experience a positive correlation was found with FA values in right AF, while severity of delusions was associated with FA values in right ILF.
In 3 studies negative symptoms were correlated negatively with FA values in some WM tracts including C, bilateral UF, CC, TL, OL, PL, FL and fibers connecting C with parahippocampal cortex; in one paper a positive correlation was found between negative symptoms and WM integrity in right I.
FA values showed a relation with clinical symptoms in right UF, CC, left ILF, left anterior limb of CI, FMJ, right AC, frontal connectivity and bilateral AF.
Cognitive function was found to be related with WM deficits in left and right UF, right CE, SLF, right AC, frontal connectivity, right anterior limb of CI (this one was found to be proportional to performance on measures of spatial and verbal declarative/episodic memory). Left thalamic FA values correlated with spatial working memory deficits. Fractional anisotropy in right rostral middle GF-striatum tract correlated positively with the number of WCST categories completed; FA reduction in LG predicted impaired processing speed while FA in left C correlated with orienting of attention. According to Marenco et al. 82 the total thalamo-cortical connectivity to PFR predicted working memory task performance.
On the contrary, according to Lee et al.65 FA in right inferior FOF had a positive relation with negative, positive symptoms and all the items of WCST; similarly, according to Choi et al.88 anterior commissure integrity correlated negatively with decision making and positively with total positive symptoms score. In UHR patients increase in FA in CC was found to be correlated with improvement in subthreshold positive symptoms while, in other samples, patients later developing psychosis had lower FA values in several tracts. In less numerous papers FA values did not differ between UHR patients that developed or not a psychotic disorder.
Functional deterioration in UHR was predicted by lower FA values in H and ILF, Goghari et al.32 didn’t find significant relationship between FA and global functioning.
On the other side, no correlation with clinical/cognitive measures were found in 8 of the studies included (2 in UHR, 3 in FEP, 3 in SZ).
Antonius et al.89 studied the relation between symptoms unawareness and WM abnormalities, suggesting that misattribution of symptoms may be implied by loss of WM integrity in right LG, TL and right precuneus.
The impact of medications on WM integrity is far from well understood. The vast majority of patients participating in DTI studies to date have been on antipsychotic medication treatment. Although medication dose or cumulative exposure do not correlate with FA in most studies; some studies reported positive findings: according to Marques et al.72 patients non-responders to treatment at baseline showed lower FA in UF, C, CC; additionally, in the same sample after 12 weeks increase in FA positively correlated to antipsychotic exposure.
Interestingly, in 2 studies FA values have been associated with metabolic measures like greater levels of LDL or polyunsaturated fatty acid concentration.
Several studies have shown age-related reduction in FA in schizophrenia, whereas other studies did not replicate this relationship. While some studies that examined correlations with age failed to identify a significant effect, 5 of the included papers showed significant negative correlation between FA and age. Additionally, SZ adults showed most FA reduction in SNC posterior region, while SZ adolescents had most FA reduction in SNC anterior region. Karlsgodt et al.14 found the absence of age-associated increase in FA in H and ILF in UHR patients.
Some studies pointed out the effect of some socio-demographic variables like gender, duration of untreated psychosis, duration of illness and age of onset on WM changes. Older age of onset tended to be associated with higher FA in ventral CI and ventral temporo-occipital WM, while adolescent-onset psychosis subjects showed WM anomalies in short association fibers connecting superior temporal gyrus and Heschl’s gyrus; suggesting that symptoms associated with TL WM anomalies including auditory hallucinations would present before FL WM symptoms including problem in executive functioning. Later age of onset was found in SZ born in winter months, SZ born in summed had lower FA in CC, bilateral inferior FOF, bilateral UF, right anterior and bilateral posterior CR, left posterior C, left posterior TR, bilateral SLF, bilateral CST and FMJ. Filippi et al. 90 found abnormalities in right anterior and posterior limb of CI, bilateral inter-hemispheric and cortico-cortical connections, cerebellum and brain stem to be related with a longer duration of untreated psychosis. Cui et al.100 showed no correlation of WM anomalies with duration of illness. No significant associations were found between FA and QI in 2 papers, but in another one SZ patients had FA values proportional to QI and differences between smoking and non-smoking SZ were no longer significant after QI correction.
Focusing particularly on patients outcome, increase in FA values in affected tracts was predictive of improvement in symptoms and good outcome, while greater WM changes in some of these tracts, like bilateral UF and bilateral SLF, were associated with poor outcome.
There is a need to better understand the relationship between neural changes with clinical manifestations, cognitive and social functioning and outcome. Understanding the progression of these changes over the span of the illness is important whilst taking into account the possible confounding effects of age, age of onset, duration of illness, sex, and treatment. This will potentially allow better staging of illness, identification of biomarkers for monitoring course of the illness as well as response to treatment.
CONCLUSIONS
In conclusion, despite heterogeneity of DTI findings in psychosis, there is mounting evidence of disruptions of white matter integrity in cortical-subcortical brain regions, as well as associative and commissural tracts, highlighting neural changes in patients affected by or at high-risk for psychosis.
Future studies need to validate these findings in larger samples of subjects and in different populations as well as chart the progress of these cerebral WM changes over time so as to better appreciate the trajectory with illness course, treatment and chronicity.
Particularly, it can be useful combining DTI studies to functional RMN methods in order to investigate mediating factors that will enhance our knowledge about pathophysiology of psychosis.
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